Use of cdp-choline for the treatment of alcohol withdrawal syndrome

ABSTRACT

The invention relates to the use of CDP-Choline or its pharmaceutically acceptable salts for the preparation of a medicinal product for the treatment of alcohol withdrawal syndrome at daily doses equivalent to 0.5-2 g of free CDP-Choline.

DESCRIPTION

[0001] The present invention relates to the use of CDP-choline for thetreatment of alcohol withdrawal syndrome.

[0002] The toxic effects of alcohol on central nervous system arebasically exerted on neuronal membrane and synapses (Leonard B. E.,Alcohol Alcohol., 1986: 21(4), 325-338). Histological alterations ofneuronal structure consist in a lesser branching of hippocampus nervecells and Purkinje's cells. Comparison of brains from healthy subjectswith those from alcoholic patients revealed a lesser branching ofpyramidal neuronal basal dendrites in upper cerebral cortex and motorcortex (Ledig M. and Mandel P., M S-Medecine Sciences, 1988: 4(6),352-357).

[0003] Chronic alcohol abuse has also been reported to impair dopaminereceptor sensitivity. This effect is probably related to changes inneuronal membrane fluidity and in the number and functionality ofreceptors, as well as to a decrease in acetylcholine reuptake anddopamine deficiency (Carlen P. L. and col., Ann. Neurol., 1981: 9(1),84-86).

[0004] CDP-choline (cytidine diphosphate choline, Citicoline) is a keyintermediate in the synthesis of structural phospholipids present in theneuronal membrane (Kennedy E. P. and Weiss S. B., J. Biol. Chem., 1956;222, 193-214) and plays an important role in its formation and repairwhen the phospholipidic structure is damaged by endogenous or exogenouscauses involving a decrease in cytidine and choline uptake.

[0005] The administration of CDP-choline enhances dopamine synthesis andrelease (Martinet M. et al., Biochem. Pharmacol., 1981: 30(5), 539-541)as well as choline and acetylcholine brain levels. The administration ofrepeated doses of CDP-choline produces an increase of brain phospholipidlevels, which is secondary to an increase of cytidine and choline plasmalevels (Agut J. et al., Ann. New York Acad. Sci., 1993: 695, 318-320).

[0006] Surprisingly, the applicants have found out that theadministration of CDP-choline to alcoholic patients reduces the durationand intensity of their withdrawal symtoms and induces an evidentrecovery in a significant proportion of patients.

[0007] The use of CDP-choline according to the present invention, whichincludes a method for treating alcohol withdrawal syndrome, comprisesthe administration of an effective amount of CDP-choline or apharmaceutically acceptable salt thereof to an alcoholic patient.

[0008] According to the present invention, CDP-choline is administeredas free compound or as a pharmaceutically acceptable salt, whether inanhydrous or hydrated form, conveniently mixed with pharmaceuticalcarriers and/or excipients, to humans at daily doses of 0.5 to 2 ginclusive in free CDP-choline, preferably from 0.5 to 1 g inclusive,both orally and parentally. Pharmaceutically acceptable salts ofCDP-choline include its alkaline or alkaline earth salts, such as itssodium, potassium, calcium and magnesium salts or its acid additionsalts with a mineral or organic acid, such as hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid,trifluoroacetic acid, citric acid, lactic acid, malonic acid, tartaricacid, acrylic acid, metacrylic acid, malic acid, maleic acid, fumaricacid, benzoic acid, salicylic acid, cinnamic acid, methane sulphonicacid, benzenesulphonic acid, p-toluensulphonic acid and nicotinic acid.

[0009] CDP-choline and its salts, whether as anhydrous or hydratedsubstances, under the invention may be administered orally in the formof tablets, capsules, powder, granules, cachets, lozenges, solution,suspension, emulsion, syrup, gel and the like; or parenterally in theform of solution, suspension, emulsion or the like for intravenous orintramuscular injection.

EXAMPLES

[0010] The present invention is illustrated by the Examples that follow.Those skilled in the art will be able to make any change provided thespecific embodiment of the invention is not modified and, therefore, theinvention is not limited to the specific details of the Examples.

Example 1 500 mg Tablets

[0011] CDP-choline, sodium salt 522.5 mg Talc  30.0 mg Magnesiumstearate  3.0 mg Silicon dioxide  2.5 mg Croscarmellose sodium  20.0 mgCorn starch  20.0 mg Microcrystalline cellulose s.q. 780.0 mg

EXAMPLE 25% Oral Solution

[0012] CDP-choline, sodium salt 26.12 g 70% Sorbitol 20.00 g Methylp-hydroxybenzoate 0.16 g Propyl p-hydroxybenzoate 0.04 g Disodiumcitrate 0.60 g Saccharin sodium 0.02 g Strawberry essence 0.04 g RedPunzo 4R 0.50 mg Anhydrous citric acid 0.05 g Purified water s.q. 100.00ml

Example 3 Solution for Injection

[0013] CDP-choline, sodium salt 522.50 mg Hydrochloric acid, pH 6.0-6.5s.q. Water for injection s.q. 4.00 ml

Example 4 Open Clinical Study of CDP-Choline in Alcohol WithdrawalSyndrome

[0014] The progress of alcohol withdrawal syndrome was assessed in anopen study conducted in 197 patients. CDP-choline was administered atdoses of 500 mg/d i.m. or 600 mg/d p.o. for 60 days. At 30 and 60 daysfollowing treatment, significant differences (p<0.001) were observed inthe assessments performed. At 60 days, 55.83% of patients had given updrinking alcohol and 31.97% of patients drank much less. A significantimprovement was observed on anxiety, tremor, disorientation, insomnia,dysarthria, tendency to suicide and neuritic pains.

Example 5 Open, Randomized, Comparative Clinical Study of CDP-Choline inAlcohol Withdrawal Syndrome Versus Clomethiazole and Vitamin B

[0015] An open, randomized and comparative study on the conventionaltherapy of alcohol withdrawal syndrome was conducted in 40 patients.Patients were randomly distributed in two groups of 20. One of thegroups was used as control and received clomethiazole and vitamin B₁, B₆and B₁₂. This treatment regimen was maintained for 8 days, and thenpatients were given diazepam until completion of treatment (60 days).The other group of patients received the same treatment regimen plusCDP-choline 500 mg i.m. every 12 h for the first 30 days and CDP-choline200 mg i.m. every 8 h for the remaining 30 days. The patients whoreceived CDP-choline plus the conventional therapy showed significantdifferences versus control at 30 days following treatment in tremorincidence (p<0.05), cramps (p<0.05), asthenia (p<0.05), emotionallability (p<0.01), nervousness (p<0.05) and social withdrawal (p<0.05).

1. The use of CDP-choline or of a pharmaceutically acceptable saltthereof for the preparation of a medicament for the treatment of alcoholwithdrawal syndrome.
 2. The use according to claim 1 in which thepharmaceutically acceptable salts of CDP-choline are it;

alkaline or alkaline earth salts or its salts with minerals or organicacids such as hydrochlroic acid, hydrobromine acid, sulphuric acid,phosphoric acid, acetic acid trifluoroacetic acid, citric acid, lacticacid, maloni

acid, tartaric acid, acrylic acid, metacrylic acid, mali

acid, maleic acid, fumaric acid, benzoic acid, salicyli

acid, cinnamic acid, methane sulphonic acid benzenesulphonic acid,p-toluensulphonic acid and nicotini

acid, in anhydrous or hydrated form.
 3. The use according to claims 1 or2 at daily dose:

in equivalent amounts of free CDP-choline ranging from


0. to 2 g.
 4. The use according to claim 3, wherein the dose:

range from 0,5 to 1 g.
 5. A method for the treatment of alcoholwithdrawal syndrome comprising administering to an alcoholic patient inneed thereof an effective amount of CDP-choline or of

pharmaceutically acceptable salt thereof.